PROJECT SUMMARY Chronic hepatitis B virus infections (CHB) are recognized as a major global health concern. CHB affects 247 million people worldwide, and 887,000 die annually from associated liver complications. This high morbidity and mortality is exacerbated by the fact that treatments for CHB are rarely curative. Thus, there remains an urgent need to develop new therapeutic treatments for CHB that will lead to clearance or lasting suppression of infection. Here, we propose a new way to target HBV through the use of MHC-E-restricted CD8+ T cells. There are only two MHC-E alleles within the human population and they are functionally equivalent. Therefore, HBV-specific CD8+ T cells restricted by MHC-E should be effective in all patients with CHB. We will characterize the T cell receptors (TCRs) of MHC-E-restricted CD8+ T cells in rhesus macaques inoculated with a rhesus CMV vector that engenders large numbers of these unique responses. We will then test the ability of these TCRs to recognize and suppress HBV infection. Given the urgent need for tractable CHB therapeutics, we believe the research proposed herein to be of the highest significance.